Pyruvate dehydrogenase inhibition

Acetyl-CoA is a potent allosteric effector of glycolysis and gluconeogenesis. It allosterically inhibits pyruvate kinase (as noted in Chapter 19) and activates pyruvate carboxylase. Because it also allosterically inhibits pyruvate dehydrogenase (the enzymatic link between glycolysis and the TCA cycle), the cellular fate of pyruvate is strongly dependent on acetyl-CoA levels. A rise in... 

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

Pyruvate Dehydrogenase Is Regulated by End-Product Inhibition Covalent Modification... 

Pyruvate dehydrogenase is inhibited by its products, acetyl-CoA and NADH (Figure 17-6). It is also regu-... 

Figure 17-6. Regulation of pyruvate dehydrogenase (PDH). Arrows with wavy shafts indicate allosteric effects. A Regulation by end-product inhibition. B Regulation by interconversion of active and inactive forms.

Arsenite and mercuric ions react with the —SH groups of lipoic acid and inhibit pyruvate dehydrogenase, as... 

Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity. It increases the transport of glucose into the cell (eg, in adipose tissue), increasing the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acids, and also converts the inactive form of pyruvate dehydrogenase to the active form in adipose tissue but not in liver. Insulin also—by its ability to depress the level of intracellular cAMP—inhibits lipolysis in adipose tissue and thereby reduces the concentration of... 

Fig. 3. Generation of propionyl-CoA from the isoleucine biosynthetic pathway. The intermediate 2-ketobutyrate can be decarboxylated by either the 2-oxoacid dehydrogenase complex or at low efficiency by the pyruvate dehydrogenase complex. Inhibition of the threonine deaminase by isoleucine and of the acetolactate synthase by herbicides are indicated with dashed arrows...

Dihydroxybenzoic acid (DHB) is also a commonly used tool to measure the pharmacological effects of HIF-la stabilization via PHD inhibition. Recently, it was shown that mice pretreated with DHB (100 mg/kg, i.p.) showed a marked resistance to the neurotoxic effects of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) via protection of dopaminergic cell loss and striatal denervation. Importantly, this protection was seen to coincide with HIF-la stabilization, and the prevention of the MPTP-induced loss of ferroportin and striatal iron. Additionally, in these studies, DHB was also observed to block MPTP-induced reduction in mitochondrial pyruvate dehydrogenase, at both the mRNA level and through the measurement of enzyme activity in midbrain substantia nigra [26]. 

Pyruvate dehydrogenase is inhibited by its product acetyl CoA. This control is important in several contexts and shoidd be considered along with pyruvate carboxylase, the other mitochondrial enzyme that uses pyruvate (introduced in gluconeogenesis, Chapter 14, Figure 1-14-5). 

In the brain, when ketones are metabolized to acetyl CoA, pyruvate dehydrogenase is inhibited. Glycolysis and subsequently glucose uptake in brain decreases. This important switch spares body protein (which otherwise would be catabolized to form glucose by gluconeogenesis in the liver) by allowing the brain to indirectly metabolize fetty acids as ketone bodies. 

Figure 16.1 The glucose/fatty add cycle. The dotted Lines represent regulation. Glucose in adipose tissue produces glycerol 3-phosphate which enhances esterification of fatty acids, so that less are available for release. The effect is, therefore, tantamount to inhibition of lipolysis. Fatty acid oxidation inhibits pyruvate dehydrogenase, phosphofructokinase and glucose transport in muscle (Chapters 6 and 7) (Randle et al. 1963).

The most important factor in the regulation of the cycle is the NADH/NAD ratio. In addition to pyruvate dehydrogenase (PDH) and oxoglu-tarate dehydrogenase (ODH see p. 134), citrate synthase and isodtrate dehydrogenase are also inhibited by NAD deficiency or an excess of NADH+HT With the exception of isocitrate dehydrogenase, these enzymes are also subject to product inhibition by acetyl-CoA, suc-cinyl-CoA, or citrate. 

High acetyl CoA levels from 3-oxidation of fatty acids in liver cells inhibit the pyruvate dehydrogenase complex and activate pyruvate carboxylase, which increases oxaloacetate synthesis. 

Acetyl-CoA is a critical regulator of the fate of pyruvate it allosterically inhibits pyruvate dehydrogenase and stimulates pyruvate carboxylase (see Fig. 15-20). In these ways acetyl-CoA prevents it own further production from pyruvate while stimulating the conversion of pyruvate to oxaloacetate, the first step in gluconeo-genesis. 

The conversion of pyruvate to acetyl CoA and C02 A. is reversible. B. involves the participation of lipoic acid. C. is activated when pyruvate dehydrogenase complex is phosphorylated by a protein kinase in the pres ence of ATP. D. occurs in the cytosol. E. depends on the coenzyme biotin. Correct answer = B. Lipoic acid is an intermedi ate acceptor of the acetyl group formed in the reaction. Pyruvate dehydrogenase complex cat alyzes an irreversible reaction that is inhibited when the enzyme is phosphorylated. The enzyme is located in the mitochondrial matrix. 

Allosteric activation of hepatic pyruvate carboxylase by acetyl CoA occurs during fasting. As a result of excessive lipolysis in adipose tis sue, the liver is flooded with fatty acids (see p. 328). The rate of for mation of acetyl CoA by p-oxidation of these fatty acids exceeds the capacity of the liver to oxidize it to C02 and H20. As a result, acetyl CoA accumulates and leads to activation of pyruvate carboxylase. [Note Acetyl CoA inhibits pyruvate dehydrogenase (see p. 108). Thus, this single compound can divert pyruvate toward gluconeogenesis and away from the TCA cycle.]... 

During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced primarily by fatty acid degradation inhibits pyruvate dehydrogenase (see p. 108), and activates pyruvate carboxylase (see p. 117). The oxaloacetate thus produced is used by the liver for gluconeogenesis rather than for the TCA cycle. Therefore, acetyl Co A is channeled into ketone body synthesis. 

Reactions of the TCA cycle Enzyme that oxidatively decarboxylates pyruvate, its coenzymes, activators, and inhibitors REACTIONS OF THE TRICARBOXYLIC ACID CYCLE (p. 107) Pyruvate is oxidatively decarboxylated by pyruvate dehydrogenase complex producing acetyl CoA, which is the major fuel for the tricarboxylic acid cycle (TCA cycle). The irreversible set of reactions catalyzed by this enzyme complex requires five coenzymes thiamine pyrophosphate, lipoic acid, coenzyme A (which contains the vitamin pantothenic acid), FAD, and NAD. The reaction is activated by NAD, coenzyme A, and pyruvate, and inhibited by ATP, acetyl CoA, and NADH. 

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